Figure 1.

TRPM2 protein structure and modulators of TRPM2 activity. Extracellular agents such as H₂O₂, ROS, TNFα, Aβ and concanavalin A enhanced TRPM2 activity via production of intracellular ADP that gates TRPM2 via binding to the NUDT9-H domain. AMP and 8-Br-cADPR reduce TRPM2 activity through interaction with the NUDT9-H domain. Protons and divalent heavy metal cations reduce TRPM2 activity through interaction with the pore region. Ca²⁺ gates TRPM2 via CaM interaction with N-terminal IQ-like motif. Structurally unrelated compounds, such as FFA, clotrimazole, 2-APB, ACA, scalaradial and AG490, 555 and 556, are also able to inhibit TRPM2, although their mechanisms of action remain to be elucidated.